The etiology of diabetic peripheral neuropathy (DPN) initiates from an inter-related series of metabolic and vascular insults that ultimately contribute to sensory neuron degeneration. In the quest to pharmacologically manage DPN, small molecule inhibitors have been developed to target proteins regarded as diabetes specific as well as those that increase in multiple disease states. Such efforts have not proven successful suggesting the identification of novel targets that play a fundamental role in regulating protein integrity and preserving nerve function in the diabetic state may represent a new paradigm. Heat shock protein 90 (Hsp90) is a molecular chaperone that binds client proteins and promotes their folding into biologically active structures. It is also the master regulator of a cytoprotective heat shock response, which aids the refolding of aggregated and damaged proteins that occur upon cell stress. Both the N- and C-terminal ATP binding domains of Hsp90 regulate its interaction with proteins. N-terminal inhibitors of Hsp90 exhibit potent cytotoxicity against tumor cells and are in clinical trials, but these compounds also induce a cytoprotective heat shock response at concentrations necessary for cytotoxicity. In contrast, we have developed potent small molecule inhibitors of the Hsp90 C-terminal domain whose neuroprotective efficacy is manifested at concentrations far below those necessary to induce neuro-toxicity. The lead compound for these inhibitors, KU- 32, is based upon novobiocin. KU-32 protects against hyperglycemia-induced death of sensory neurons and can attenuate several physiologic indices of DPN in mice through induction of the heat shock response. Unfortunately, this molecule requires significant synthetic preparation, thus preventing full elucidation of structure-activity relationships and limiting its use in animals/humans. Thus, the goal of this proposal is to provide new compounds derived from KU-32 that exhibit better neuroprotective activity and can be prepared in a minimal number of synthetic procedures. An initial screen will identify compounds with increased efficacy relative to KU-32 and lead candidates will be tested for protection against glycemic stress of sensory neurons, followed by animal studies of DPN in both wild-type and Hsp70 knockout mice. The outcome of this work will further develop and identify small molecule C-terminal Hsp90 inhibitors that decrease neurodegeneration in the absence of significant neurotoxicity. PUBLIC HEALTH RELEVANCE: Diabetic neuropathy is a common complication of diabetes that develops in about 60% of the approximately 24 million Americans afflicted with diabetes. Despite the impact of diabetic neuropathy on decreasing the quality of life, the existing FDA approved treatments are limited to drugs originally targeted to treat depression (Cymbalta) and convulsions (Lyrica). This project focuses on optimizing the effectiveness of a new class of therapeutics for the direct treatment of diabetic neuropathy.